In mammals, bone is lost rapidly during lactation and recovers fully after weaning. This reproductive cycle of skeletal catabolism and anabolism is well documented, but little is known about the mechanisms stimulating the anabolic response of the skeleton to weaning. Our preliminary data show that murine bone turnover is elevated during lactation. Weaning results in the sudden disappearance of osteoclasts and a further boost in the number and activity of osteoblasts. We believe that this sudden uncoupling of bone turnover in favor of bone formation initiates the anabolic response. The sequence of events that lead to this dramatic shift in bone metabolism are not known. Our data and those of others have shown that while during lactation PTHrP levels rise and estrogen levels are low, weaning is characterized by a rise in circulating estrogen and calcium and a fall in PTHrP levels. In addition, we have observed an activation of the canonical Wnt signaling system in the skeleton after weaning. The relevance and purpose of our study is to uncover mechanisms that regulate this intense anabolic activity in bone. We hope to learn to exploit this anabolic response in order to heal osteoporosis in all age groups. We will approach this goal through two specific aims. Aim 1 will examine the systemic signals that contribute to the dramatic disappearance of osteoclasts after weaning and regulation of the decrease in bone resorption by manipulating estrogen, PTHrP and calcium levels in lactating and weaned mice. Aim 2 will examine the effects of Wnt signaling in regulating bone formation and osteoblast function after weaning. We will use a bi-transgenic, tetracycline regulated system to deliver the Wnt antagonist, DKK1, to bone cells specifically at the time of weaning. Our goal will be to determine if blocking Wnt signaling inhibits bone formation after weaning. The candidate is a junior faculty member in the section of Pediatric Endocrinology at Yale University. Her career goal is to become an independent investigator in metabolic bone diseases. She will benefit from guidance and mentorship of Dr. John Wysolmerski, who is an accomplished researcher in this area. The strength of departments of adult and pediatric endocrinology in bone research will also put the candidate in a position of strength to pursue her career.